Our major focus has been to identify and characterize translocations to the IgH locus (chromosome 14q32.3) in multiple myeloma (MM) cell lines and tumors. Karyotypic 14q32 translocations have been identified in 20-30% of karyotypically abnormal MM tumors, but apart from 11q13 the partner chromosome is rarely identified (thus designated 14q+). Hypothesizing that IgH translocations will be mediated mainly by aberrant IgH switch recombination, we developed a comprehensive Southern blot assay to identify rearranged illegitimate switch recombination fragments (ISRF) that contain sequences from only 1 switch region. Of 18 ISRFs identified and characterized in MM cell lines, 16 have been determined by cloning (9 in 8 MM lines) or mapping to be translocations of another chromosome to an IgH switch region. In a panel of 21 MM lines, 19 have either an ISRF (15 lines) or a karyotypic 14q32 translocations (12 lines). The translocation breakpoints are present in primary tumors (confirmed for tumors that generated 3 MM lines, cloned from one primary tumor, and ISRFs in a high proportion of other tumors). We have 4 conclusions regarding IgH translocations in MM: 1) they occur almost universally, indicating the unreliability of karyotypic analysis in MM; 2) they occur principally into or near IgH switch regions; 3) they involve a diverse but non-random (4p16 or 11q13 in about 50% of tumors) array of chromosomal partners; and 4) dysregulation of cyclin D1 (11q13) and FGFR3 (4p16.3) each occur in about 25% of MM tumors. A minor focus is to determine the generality and significance of our finding that there is selective expression of one c-myc allele in 2 informative MM cell lines despite the apparent absence of translocation, rearrangement, or amplification involving the c-myc locus.